Publikationsserver der RWTH Aachen University
Unterschiede in der TGF-[beta]-vermittelten Signaltransduktion in aktivierten hepatischen Sternzellen unterhalb der Smad2-Phosphorylierung
Abstract
dc:descriptionTGF-beta is a multifunctional cytokine, that regulates cell proliferation, differentiation, and extracellular matrix production. A profibrogenic role of TGF-beta is postulated, but pathways targeting the TGF-beta response to specific gene activities involved in phenotypic changes of hepatic stellate cells (HSC) have not been characterized in detail. We investigated TGF-beta1-responsiveness of activated HSC and determined Smad2 as intracellular mediator. Gene expression and reporter gene analysis showed, that TGF-beta1 treatment lead to upregulation of PAI-1, Smad7 and (CAGA)9-MLP-Luc subsequent to Smad2 phosphorylation. Two further TGF-beta responsive genes, TIMP-1 and type I collagen were not affected. In contrast to primary cultured HSC, which were inhibited in their growth, TGF-beta1 did not influence the proliferation rate of HSC-T6 and CFSC, two permanent cell lines, which both resemble phenotypes of activated HSC. Ectopic expression of Smad7 was able to inhibit TGF-beta-dependent Smad2 phosphorylation and stimulation of (CAGA)9-MLP-Luc, but had no effect on collagen expression. Surprisingly, Smad7 did not block TGF-beta dependent stimulation of PAI-1 expression or p3TPluc activation in these cells. Furthermore, both HSC-lines displayed constitutively phosphorylated Smad3, whose origin remains to be determined and functional relevance is discussed. We conclude, that regulation of TGF-beta actions in activated HSC is complex and involves multiple signaling pathways. Depending on the target gene, different signal transducers and factors may be involved and, therefore, TGF-beta-based therapies have to be carefully tailored.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2003
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Berg, Frank
- Contributors dc:contributor
-
- Dooley, Steven
Subjects
dc:subject × 6Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger
Identifiers
dc:identifier.*- OAI identifier oai:identifier
- oai:publications.rwth-aachen.de:61926